Faculty Bibliography

Autologous stem cell transplant (ASCT) remains standard of care for consolidation after induction therapy for eligible newly diagnosed myeloma patients. In recent clinical trials comparing ASCT to delayed ASCT, patients aged over 65 were excluded. In real-world practice stem cell transplants are not restricted to those aged under 65 and clinicians decide on transplant eligibility based on patient fitness rather than a strict age cut off. Data from the UK NCRI Myeloma XI trial, a large phase III randomised controlled trial with pathways for transplant-eligible (TE) and ineligible (TNE) patients, was used in an exploratory analysis to examine the efficacy and toxicity of ASCT in older patients including analysis using an agematched population to compare outcomes for patients receiving similar induction therapy with or without ASCT. Older patients within the TE pathway were less likely to undergo stem cell harvest at the end of induction than younger patients and of those patients undergoing ASCT there was a reduction in PFS associated with increasing age. ASCT in older patients was well tolerated with no difference in morbidity or mortality between patients aged.

BACKGROUND:The tumor microenvironment (TME) is increasingly appreciated as an important determinant of cancer outcome, including in multiple myeloma (MM). However, most myeloma microenvironment studies have been based on bone marrow (BM) aspirates, which often do not fully reflect the cellular content of BM tissue itself. To address this limitation in myeloma research, we systematically characterized the whole bone marrow (WBM) microenvironment during premalignant, baseline, on treatment, and post-treatment phases. METHODS AND FINDINGS/RESULTS:Between 2004 and 2019, 998 BM samples were taken from 436 patients with newly diagnosed MM (NDMM) at the University of Arkansas for Medical Sciences in Little Rock, Arkansas, United States of America. These patients were 61% male and 39% female, 89% White, 8% Black, and 3% other/refused, with a mean age of 58 years. Using WBM and matched cluster of differentiation (CD)138-selected tumor gene expression to control for tumor burden, we identified a subgroup of patients with an adverse TME associated with 17 fewer months of progression-free survival (PFS) (95% confidence interval [CI] 5-29, 49-69 versus 70-82 months, χ2 p = 0.001) and 15 fewer months of overall survival (OS; 95% CI -1 to 31, 92-120 versus 113-129 months, χ2 p = 0.036). Using immunohistochemistry-validated computational tools that identify distinct cell types from bulk gene expression, we showed that the adverse outcome was correlated with elevated CD8+ T cell and reduced granulocytic cell proportions. This microenvironment develops during the progression of premalignant to malignant disease and becomes less prevalent after therapy, in which it is associated with improved outcomes. In patients with quantified International Staging System (ISS) stage and 70-gene Prognostic Risk Score (GEP-70) scores, taking the microenvironment into consideration would have identified an additional 40 out of 290 patients (14%, premutation p = 0.001) with significantly worse outcomes (PFS, 95% CI 6-36, 49-73 versus 74-90 months) who were not identified by existing clinical (ISS stage III) and tumor (GEP-70) criteria as high risk. The main limitations of this study are that it relies on computationally identified cell types and that patients were treated with thalidomide rather than current therapies. CONCLUSIONS:In this study, we observe that granulocyte signatures in the MM TME contribute to a more accurate prognosis. This implies that future researchers and clinicians treating patients should quantify TME components, in particular monocytes and granulocytes, which are often ignored in microenvironment studies.

Renal injury is a common complication of multiple myeloma (MM) and is associated with adverse outcome. Despite this, the natural history of renal injury in patients with MM remains uncertain especially in the context of intensive therapy and novel therapies. To address the lack of data, we evaluated the renal function of 2334 patients from the UK National Cancer Research Institute Myeloma XI trial at baseline and at 12 months to assess renal function over time and the factors associated with change. Patients who had severe acute kidney injury or a requirement for dialysis were excluded. At 12 months of the 1450 evaluable patients planned for autologous transplantation; 204 (14%) patients had a decline in estimated glomerular filtration rate (eGFR) ≥25% from baseline, 341 (23.5%) had an improvement and 905 (62%) had no significant change in eGFR. Renal outcome at 12 months for the 884 evaluable patients who were not planned for transplant was similar. Improved renal function was more likely if patients were <70 years old, male, had an average eGFR <60 mL per minute per 1.73 m2 and a higher baseline free light chain level >1000 mg/L, and/or a free light chain response of >90%. It did not correlate with monoclonal-protein response, transplantation, or use of a bortezomib-based regimen. We show that with current therapies the proportion of patients who have a significant decline in renal function in the first 12 months is small. The greatest relative improvement in eGFR is seen in patients with high free light chain at baseline and a high light chain response. This trial was registered at http://www.isrctn.com as #49407852.

Preclinical data suggests that bortezomib can inhibit genotoxic stress response pathways and thereby restore sensitivity to DNAdamaging chemotherapeutic agents. This was the rationale for this study combining bortezomib with two chemotherapy agents. The trial recruited patients from 2006 to 2013 but has never been analysed or reported and provides insights into the role of standard chemotherapy agents in relapsed myeloma, for which there is little published evidence. VIM was a single centre phase 1/2 study of bortezomib, idarubicin and melphalan in relapsed or refractory myeloma. Phase 1 was a 3+3 design with escalating doses of idarubicin and melphalan in combination with 1.3 mg/m2 bortezomib administered on D1,4,8,11 on a 4 weeks cycle. Phase 2 was dose expansion at the maximum tolerated dose (MTD) in a further 20 patients to explore efficacy. Treatment was for 3 cycles. Following VIM, patients were allowed to directly proceed to other treatments including autologous transplant (ASCT). The primary objective was safety and tolerability. Secondary endpoints were response, Progression Free and Overall Survival (PFS, OS). Key inclusion criteria were relapsed or refractory myeloma following >=1 previous therapies, platelet count >=70 x109/L, white cell count >=3.0 x109/L and creatinine clearance of >=40 mls/min. Dose limiting toxicity was defined as any grade 4 non-haematological toxicity, any grade 3 nonhaematological toxicity not resolving to grade 2 within 2 weeks of end of cycle and any grade 4 haematological toxicity except neutropenia not resolving to grade 3 within 2 weeks of end of cycle. The study recruited 3, 3, 7 patients on dose levels 1, 2 and 3 respectively during the dose escalation phase. The MTD dose was defined as level 2 which was: Idarubicin 5 mg/m2 PO D4, 5; melphalan 15 mg/m2 IV D4; bortezomib 1.3 mg/m2 D1, 4, 8, 11 on a 4 weeks cycle. An additional 20 patients were recruited to the dose expansion phase. Median patient age was 62. Median prior lines of therapy was 4 (range 2-8). Adverse Events at the MTD level are listed in table 1. The main toxicity was haematological, with 74% of patients having grade >=3 neutropenia, 78% grade >=3 thrombocytopenia. 26% of patients experienced grade >=3 infective complications. There were 3 deaths on treatment; all had progressive or refractory disease at time of death, two with concurrent respiratory infection but neither were neutropenic or directly treatment related. In the intention to treat (ITT) cohort, the overall response rate (ORR) was 79%, with 46% achieving >=very good partial response (VGPR) of which 14% were near complete response (nCR, defined as no paraprotein by serum protein electrophoresis and <5% plasma cells on trephine but without immunofixation to confirm CR). In the MTD cohort the ORR was 85%, with 50% >=VGPR and 20% nCR. PFS reflects the heterogeneity of treatment after VIM, including ASCT. Median OS was 19.0 months in the ITT cohort and 26.1 months in the MTD cohort. Treatment options at relapse have multiplied since this trial was designed. However, VIM is a generic, relatively inexpensive, steroid free regimen with defined toxities and significant efficacy. The main side effects, as expected, were haematological. Responses were higher than expected for median 5th line therapy suggesting possible synergy in this combination and reminding us that standard chemotherapies can have a role in relapsed myeloma if other options are unavailable and blood counts are reasonable

BACKGROUND:Multiple Myeloma (MM) is a hematological malignancy with genomic heterogeneity and poor survival outcome. Apart from the central role of genetic lesions, epigenetic anomalies have been identified as drivers in the development of the disease. METHODS:Alterations in the DNA methylome were mapped in 52 newly diagnosed MM (NDMM) patients of six molecular subgroups and matched with loci-specific chromatin marks to define their impact on gene expression. Differential DNA methylation analysis was performed using DMAP with a ≥10% increase (hypermethylation) or decrease (hypomethylation) in NDMM subgroups, compared to control samples, considered significant for all the subsequent analyses with p<0.05 after adjusting for a false discovery rate. RESULTS:We identified differentially methylated regions (DMRs) within the etiological cytogenetic subgroups of myeloma, compared to control plasma cells. Using gene expression data we identified genes that are dysregulated and correlate with DNA methylation levels, indicating a role for DNA methylation in their transcriptional control. We demonstrated that 70% of DMRs in the MM epigenome were hypomethylated and overlapped with repressive H3K27me3. In contrast, differentially expressed genes containing hypermethylated DMRs within the gene body or hypomethylated DMRs at the promoters overlapped with H3K4me1, H3K4me3, or H3K36me3 marks. Additionally, enrichment of BRD4 or MED1 at the H3K27ac enriched DMRs functioned as super-enhancers (SE), controlling the overexpression of genes or gene-cassettes. CONCLUSIONS:Therefore, this study presents the underlying epigenetic regulatory networks of gene expression dysregulation in NDMM patients and identifies potential targets for future therapies.

Background: Patients with relapsed and refractory multiple myeloma (RRMM) who are triple-class exposed to immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs) have limited treatment options and poor outcomes. The BCMA- targeted CAR T cell therapy idecabtagene vicleucel (ide-cel; bb2121) is being developed to address the unmet need in this setting. Initial results from the ongoing phase II KarMMa study (NCT03361748), in which ide-cel is being investigated in patients with RRMM who had >=3 prior regimens (including an IMiD, a PI, and an anti-CD38 mAb) and were refractory to their last regimen per IMWG criteria, have been released. A systematic literature review identified 2 phase II clinical trials investigating the efficacy and safety of specific therapies under US FDA evaluation in this setting, namely selinexor plus dexamethasone (Sd; NCT02336815) and belantamab mafodotin 2.5 mg/kg (BM; NCT03525678).
Aim(s): To compare the efficacy outcomes of ide-cel from the ongoing KarMMa study with 1) Sd from STORM part 2 and 2) BM from DREAMM-2.
Method(s): Unanchored matching-adjusted indirect treatment comparisons were performed based on individual patient-level data from 128 infused patients in KarMMa and study-level data from 1) STORM part 2 and 2) DREAMM-2. Individual patient data were reconstructed based on the published Kaplan-Meier curves for time-to-event outcomes from the external studies. Between-study differences were summarized, and the most relevant differences in patient characteristics were identified from the literature and based on clinical expertise. Propensity score models were used to weight patients in KarMMa to predict outcomes in a population corresponding to each external study. Odds ratios were calculated for overall response rate (ORR) using weighted logistic regression models. Hazard ratios (HRs) were calculated for progression-free survival (PFS) and overall survival (OS) using weighted Cox proportional hazard models. Sensitivity analyses were performed to explore the relative treatment effects with other cohorts from the KarMMa trial, including the enrolled patients (N = 140) and patients receiving the target dose of 450 x 106 CAR+ T cells (N = 54).
Result(s): Ide-cel was associated with a higher ORR compared with both Sd and BM in a population matched to each external trial (Table). Similarly, ide-cel extended PFS and OS vs both Sd and BM. Results were generally consistent in the sensitivity analyses using the KarMMa enrolled population and also across different doses for both indirect comparisons, although the effective sample size was reduced substantially in some cases. Summary/Conclusion: Results from the matching-adjusted indirect comparison suggest that ide-cel offers improvements in efficacy compared with both Sd and BM, the only therapies for which there are currently phase II data in RRMM patients after anti-CD38 mAb treatment

Background: Patients (pts) who are triple-class-exposed to immunomodulatory drugs, proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs) have poor clinical outcomes on subsequent lines of treatment and limited treatment options.
Aim(s): To identify published evidence for therapies that have been investigated or currently used in triple-class exposed pts with relapsed and refractory multiple myeloma (RRMM).
Method(s): Searches were performed 6 January 2020 in Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials databases. Eligible studies had to have been completed <=5 years before the search date. Relevant conference proceedings for 2018 and 2019 were also included in the search. Study quality assessment included use of the Downs and Black checklist. Studies that did not explicitly require previous anti- CD38 mAb exposure but reported the proportion of pts who received this drug class were included.
Result(s): There were 24 studies identified; 11 real-world studies and 13 clinical trials. The Monoclonal Antibodies in Multiple Myeloma: Outcomes after Therapy Failure (MAMMOTH), a retrospective chart review of MM pts from 14 US academic centers, was the largest real-world study (Leukemia. 2019;33:2266-75). All pts (N = 275) were refractory to daratumumab or isatuximab and 249 received subsequent therapy after anti-CD38 therapy. The overall response rate (ORR) to the first regimen after anti-CD38 therapy was 31% overall and was 29% in the combined triple-refractory and quad-refractory subgroup (N = 148). Median progression-free survival (PFS) and overall survival (OS) after subsequent therapy was 3.4 and 9.3 months, respectively, among those who received >=1 subsequent regimen in the overall population. Other real-world studies were limited to abstracts or had a high risk of bias; ORR and median OS rarely exceeded 30% and 10 months, respectively. Three phase II clinical trials evaluated interventions that are approved or under consideration by the US FDA. STORM part 1 and part 2, assessed selinexor plus dexamethasone, a combination granted accelerated approval in the US for a highly refractory post-daratumumab population (RRMM pts with >=4 prior regimens and refractory to >=2 PIs, >=2 immunomodulatory drugs, and an anti-CD38 mAb); STORM part 2, which also included pts triple-class exposed to daratumumab, an immunomodulatory drug, and a PI (N = 122), reported an ORR of 26% and a complete response rate of 2%. The median duration of response was 4.4 months, median PFS was 3.7 months, and median OS was 8.6 months. The other phase II study, DREAMM-2, investigated belantamab mafodotin, an antibody-drug conjugate targeting B-cell maturation antigen (BCMA) in RRMM. This study evaluated 196 pts refractory to immunomodulatory drugs and PIs, and refractory/ intolerant to an anti-CD38 mAb. After a median follow-up of 6.3 months (2.5 mg/kg cohort, n = 97) and 6.9 months (3.4 mg/kg cohort, n = 99), ORR was 31% and 34%, respectively. Median PFS was 2.9 months (2.5 mg/kg) and 4.9 months (3.4 mg/kg). Median OS was not reported. Summary/Conclusion: Results from this systematic literature review (SLR) indicate that only limited efficacy data are available for therapies investigated in RRMM pts who have had prior exposure to an immunomodulatory agent, a PI, and an anti-CD38 mAb. Outcomes are generally poor, supporting an urgent need for better treatment options for triple-class-exposed pts with RRMM. The studies identified in this SLR provide a benchmark against which therapies in development, such as emerging BCMA-directed therapies, can be compared

IMPORTANCE/OBJECTIVE:New York City is a global epicenter for the SARS-CoV-2 outbreak with a significant number of individuals infected by the virus. Patients with multiple myeloma have a compromised immune system, due to both the disease and anti-myeloma therapies, and may therefore be particularly susceptible to coronavirus disease 2019 (COVID-19); however, there is limited information to guide clinical management. OBJECTIVE:To assess risk factors and outcomes of COVID-19 in patients with multiple myeloma. DESIGN/METHODS:Case-series. SETTING/METHODS:Five large academic centers in New York City. PARTICIPANTS/METHODS:Patients with multiple myeloma and related plasma cell disorders who were diagnosed with COVID-19 between March 10th, 2020 and April 30th, 2020. Exposures: Clinical features and risk factors were analyzed in relation to severity of COVID-19. Main Outcomes and Measures: Descriptive statistics as well as logistic regression were used to estimate disease severity reflected in hospital admissions, intensive care unit (ICU) admission, need for mechanical ventilation, or death. RESULTS:Of 100 multiple myeloma patients (male 58%; median age 68, range 41-91) diagnosed with COVID-19, 74 (74%) were admitted; of these 13 (18%) patients were placed on mechanical ventilation, and 18 patients (24%) expired. None of the studied risk factors were significantly associated (P>0.05) with adverse outcomes (ICU-admission, mechanical ventilation, or death): hypertension (N=56) odds ratio (OR) 2.3 (95% confidence interval [CI] 0.9-5.9); diabetes (N=18) OR 1.1 (95% CI 0.3-3.2); age >65 years (N=63) OR 2.0 (95% CI 0.8-5.3); high dose melphalan with autologous stem cell transplant <12 months (N=7) OR 1.2 (95% CI 0.2-7.4), IgG<650 mg/dL (N=42) OR=1.2 (95% CI 0.4-3.1). In the entire series of 127 patients with plasma cell disorders, hypertension was significantly associated with the combined end-point (OR 3.4, 95% CI 1.5-8.1). CONCLUSIONS AND RELEVANCE/CONCLUSIONS:Although multiple myeloma patients have a compromised immune system due to both the disease and therapy; in this largest disease specific cohort to date of patients with multiple myeloma and COVID-19, compared to the general population, we found risk factors for adverse outcome to be shared and mortality rates to be within the higher range of officially reported mortality rates.

Newly diagnosed multiple myeloma (NDMM) patients treated with immunomodulatory drugs (IMiDs) are at high venous thrombosis (VTE) risk, but data are lacking from large prospective cohorts. We present thrombosis outcome data from Myeloma IX (n=1936) and Myeloma XI (n=4358), phase III randomized controlled trials for NDMM, treating transplant-eligible and ineligible patients before and after publication of thrombosis prevention guidelines. In Myeloma IX, compared to CTD (cyclophosphamide, thalidomide and dexamethasone), transplant-eligible patients randomized to CVAD induction (cyclophosphamide, vincristine, doxorubicin and dexamethasone) had higher VTE risk (22.5%(n=121/538) vs 16.1%(n=89/554), aHR:1.46,95%CI:1.11-1.93). For transplant-ineligible patients, compared to MP (melphalan and prednisolone), patients randomized to CTDa (attenuated CTD) induction had higher VTE risk (16.0%(n=68/425) vs 4.1%(n=17/419), aHR:4.25,95%CI:2.50-7.20). In Myeloma XI, there was no difference in VTE or arterial thrombosis risk between transplant-eligible pathways, CRD (cyclophosphamide, lenalidomide and dexamethasone) and CTD (VTE:12.2%(n=124/1014) vs 13.2%(n=133/1008), aHR:0.92,95%CI:0.72-1.18; arterial events:1.2%(n=12/1014) vs 1.5%(n=15/1008), aHR:0.80,95%CI:0.37-1.70). For transplant-ineligible patients, there was no difference in VTEs between CRDa (attenuated CRD) and CTDa (10.4%(n=95/916) vs 10.7%(n=97/910), aHR:0.97, 95%CI:0.73-1.29). However, arterial risk was higher with CRDa than CTDa (3.1%(n=28/916) vs 1.6%(n=15/910), aHR:1.91,95%CI:1.02-3.57). Thrombotic events occurred almost entirely within 6m of treatment initiation. Thrombosis was not associated with inferior progression-free or overall survival (OS), apart from inferior OS for patients with arterial events (aHR:1.53, 95%CI:1.12-2.08) in Myeloma XI. The Myeloma XI trial protocol incorporated IMWG thrombosis prevention recommendations and compared to Myeloma IX, more patients were on thromboprophylaxis (80.5% vs 22.3%) with lower VTE rates for identical regimens (CTD:13.2% vs 16.1%, CTDa:10.7% vs 16.0%). However, thrombosis remained frequent in spite of IMWG-guided thromboprophylaxis, suggesting new approaches are needed.